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Several researchers in the Nuffield Department of Clinical Neurosciences appear in the 2014 ‘Highly-Cited Researchers’ list published by Thompson Reuters, the world’s leading source of intelligent information for businesses and professionals.
AL amyloidosis presenting with isolated lumbosacral radiculoplexus neuropathy
A 45-year-old man presented with an isolated sciatic mononeuropathy, which then evolved into a lumbosacral radiculoplexus neuropathy. His initial symptoms included lower limb pain, sensory disturbance and later weakness, without autonomic dysfunction. Neurophysiology suggested a postganglionic neuropathy. MR and ultrasound scans of the thighs showed right sciatic nerve thickening, and CSF analysis showed albuminocytological dissociation. Fluorodeoxyglucose positron emission tomography (FDG PET) was unremarkable. He then developed orthostatic symptoms and urinary disturbance, and was found to have an IgM paraprotein. Fat aspirate, cardiac and whole-body imaging found no amyloid deposition, and genetic testing for transthyretin amyloidosis was negative. A bone marrow biopsy was unremarkable. However, neuropathology review of a proximal, fascicular nerve biopsy identified a lambda chain-restricted plasma cell population with positive Congo red staining, leading to a diagnosis of peripheral nerve restricted amyloid light amyloidosis. We discuss the diagnostic approach to this case from the perspectives of neurology, neurophysiology, radiology and neuropathology.
Plasma periaxin is a biomarker of peripheral nerve demyelination
Abstract Assessing disease progression and informing clinical trials in peripheral neuropathy would benefit from objective and responsive fluid biomarkers closely linked to disease biology. This is particularly important in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS), the most common inflammatory neuropathies, where reliable biomarkers of peripheral demyelination would help identify, and potentially measure, active disease and responses to treatment. We postulated that periaxin, a protein exclusively expressed by myelinating Schwann cells, could serve as a fluid biomarker of demyelinating peripheral neuropathy. We developed a Simoa-based immunoassay to measure plasma periaxin in patients with CIDP (n = 45, including longitudinal samples across a discovery cohort and a validation cohort, for a total of 77 time points), GBS (n = 30, 66 time points), Charcot-Marie-Tooth disease (CMT, n = 20), central nervous system (CNS) disease controls with multiple sclerosis (MS, n = 30), and healthy controls (HC, n = 30). We also evaluated whether periaxin is released in myelinating cocultures following immune-mediated demyelination and axonal damage, comparing results with uninjured cultures. Plasma periaxin effectively distinguishes peripheral from central nervous system diseases, with significantly elevated levels in CIDP, GBS, and CMT, but not in CNS disease or healthy controls (all P < 0.01). In CIDP, periaxin discriminates patients with active disease from those with inactive disease (P < 0.0001), and plasma levels decrease following treatment with intravenous immunoglobulin (IVIg). Elevated periaxin strongly predicts clinical worsening at 1 year [sensitivity 99%, specificity 72%, area under the curve (AUC) 0.86 (95% C.I. 0.67–1)]. In GBS, peak levels of plasma periaxin and the ratio of periaxin to axonal biomarkers [neurofilament light chain (NfL) and peripherin] discriminate most cases of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) from acute motor axonal neuropathy (AMAN), as classified by electrophysiology (sensitivity 100%, specificity 86%, AUC = 0.94, 95% CI 0.81-1). Serial measurements showed that plasma periaxin levels peak 2 to 3 weeks after GBS symptom onset, followed by a gradual decline in the weeks thereafter. In vitro, periaxin is higher following immune-mediated demyelination compared to axonal damage and control conditions. Plasma periaxin is a biomarker of peripheral nerve demyelination. Combined with axonal fluid biomarkers and existing clinical scales, periaxin has the potential to improve the clinical management of peripheral neuropathies, accelerating advances in care and experimental research.
Treatment of CIDP
Chronic inflammatory demyelinating polyneuropathy is a disabling but treatable disorder. However, misdiagnosis is common, and it can be difficult to optimise its treatment. Various agents are used both for first and second line. First-line options are intravenous immunoglobulin, corticosteroids and plasma exchange. Second-line therapies may be introduced as steroid-sparing agents or as more potent escalation therapy. It is also important to consider symptomatic treatment of neuropathic pain and non-pharmacological interventions. We discuss the evidence for the various treatments and explain the practicalities of the different approaches. We also outline strategies for monitoring response and assessing the ongoing need for therapy.
Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease
The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments.
Diagnosis and Management of Multifocal Motor Neuropathy in the United Kingdom: A Multicentre Survey
ABSTRACTBackgroundWe conducted a survey to determine the current diagnosis and treatment of multifocal motor neuropathy (MMN) in the United Kingdom.MethodsDemographic, diagnostic and treatment data were collected at nine UK neuroscience centres.ResultsNinety‐five subjects were included. Mean age at diagnosis was 49.9 years (SD: 11.4). Males were more commonly affected (ratio: 1.9:1). Diagnostic delay was > 1 year from the time of first neurological assessment, in > 50% of subjects. Applying modified EFNS/PNS 2010 criteria, 69/95 (72.6%) had definite MMN, 10/95 (10.5%) had probable MMN, 15/95 (15.8%) had possible MMN, through treatment responsiveness in 9/15 (60%) and 1/95 (1.1%) did not meet criteria. Cerebrospinal fluid examination, anti‐GM1 antibody testing and brachial plexus magnetic resonance imaging were non‐contributory. Immunoglobulin response was reported in 90/92 subjects (97.8%), and 84/90 (93.3%) remained on treatment after a mean of 9.4 years, at a mean dose of 26.2 g/week (range: 4–114). Mean long‐term immunoglobulin dose was 30%–60% higher than reported in neighbouring countries. Contrasting with previous reports of frequent loss of immunoglobulin response and functional decline, our physician‐assessed long‐term outcome was favourable (stable or improving) in 74/84 (88.1%) treated subjects.InterpretationMMN diagnosis and treatment in the United Kingdom are comparable to that of neighbouring countries and follow existing guidelines. Diagnostic delay after the first neurological assessment is considerable. Electrophysiology shows at least one definite/probable conduction block in nearly 90% of cases. The mean long‐term immunoglobulin dose is higher in the United Kingdom than reported elsewhere, although highly variable. Whether higher doses of immunoglobulin may improve long‐term outcomes requires further study.
Guillain‐Barré syndrome: a comprehensive review
AbstractGuillain‐Barré syndrome (GBS) is a potentially devastating yet treatable disorder. A classically postinfectious, immune‐mediated, monophasic polyradiculoneuropathy, it is the leading global cause of acquired neuromuscular paralysis. In most cases, the immunopathological process driving nerve injury is ill‐defined. Diagnosis of GBS relies on clinical features, supported by laboratory findings and electrophysiology. Although previously divided into primary demyelinating or axonal variants, this dichotomy is increasingly challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma exchange remain the primary modalities of treatment, regardless of the electrophysiological subtype. Most patients recover, but approximately one‐third require mechanical ventilation, and 5% die. Disease activity and treatment response are currently monitored through interval neurological examination and outcome measures, and the potential role of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being explored but none have yet modified clinical practice. This review provides a comprehensive update on the pathological and clinical aspects of GBS for clinicians and scientists.
Enhanced adenoviral reactivity in Guillain-Barré syndrome after SARS-CoV-2 infection and vaccination
Abstract Case reports and series suggested an association between SARS-CoV-2 and Guillain-Barré syndrome (GBS). However, the GBS epidemic which was predicted from early risk estimates did not materialise in overall case numbers, and no plausible mechanism for any link has been established. An increased risk of GBS following adenoviral vector-based COVID-19 vaccination has been more consistently demonstrated, but a pathophysiological explanation for this association has also not yet emerged. Here, we sought to identify whether patients with GBS following COVID-19 infection or vaccination had any distinct clinical or serological features differentiating them from one another or non-pandemic GBS, and to explore the potential mechanisms of any associations. Between March 2020 and October 2021, sera from patients with GBS (n=64) and controls (n=70) were collected. Clinical features were retrieved from medical records. GBS cases were evaluated for diagnostic certainty by Brighton criteria and classified as non-COVID-19 associated (GBS-NC, n=20), GBS after COVID-19 infection (GBS-AC, n=10), or GBS after COVID-19 vaccination (GBS-AV, n=34). The humoral responses to SARS-CoV-2 proteins and putative peripheral nerve antigens, and the cytokine profile of each group were established and compared. Antibodies cloned from the acute-phase plasmablasts of an individual with GBS-AC were also assessed for reactivity against SARS-CoV-2 and peripheral nerve antigens. Sera from GBS patients and from individuals who received COVID-19 vaccinations (n=36: 16 ChAdOx1, 10 Ad26.COV2.S/Janssen, and 10 Tozinameran/Pfizer–BioNTech) without developing GBS were tested for IgG reactivity against SARS-CoV-2 and adenoviral proteins. There were no clinical differences between the GBS groups. Patients with GBS-AC had a greater IgG reactivity to the S1 component of the SARS-CoV-2 spike protein compared to non-GBS COVID-19 controls. A minority of antibodies from cloned plasmablasts targeted SARS-CoV-2 proteins but there was no reactivity or cross reactivity with peripheral nerve antigens or tissue. There were no other serological or immunological differences between the GBS groups. However, when compared to uncomplicated vaccine recipients, GBS patients in toto, and each group individually, demonstrated significantly greater antibody reaction to a range of human adenoviral proteins. Compared to controls exposed to the same immunological stimulus, antibody reactivities to viral antigens are enhanced in patients with GBS. However, we found no mechanistic link between S1 and peripheral nerve reactivity or pathology. Serological responses to adenoviral proteins may be directly involved in the pathogenesis of Guillain-Barré syndrome, potentially contributing to cases with currently unexplained aetiology.
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) Developing During Tacrolimus Treatment: A Case Series
ABSTRACTIntroduction/AimsChronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) can occasionally emerge during treatment with tacrolimus, a commonly used immunosuppressant for solid organ transplantation, and this association is poorly recognized. We describe the clinical presentation, investigations, and disease course of a series of patients who developed CIDP during tacrolimus treatment.MethodsThis is a retrospective case series of six patients with electrophysiologically confirmed CIDP (=2021 EFNS/PNS criteria) during tacrolimus use for solid organ transplantation, evaluated at two UK National Health Service (NHS) trusts between 2017 and 2023. We describe the clinical characteristics, laboratory investigations, neurophysiological features, treatment response, and association with tacrolimus treatment.ResultsCIDP was diagnosed between 5 months and 13 years after initiation of tacrolimus, post cardiac (2), renal (2), lung (1), and combined kidney‐pancreas (1) transplantation. All patients met diagnostic criteria for CIDP. 5/6 patients improved clinically following intravenous immunoglobulin (IVIg). 4/6 patients were switched to either sirolimus or azathioprine without evidence of active disease despite no further treatment. 2/6 patients continued tacrolimus, and both required ongoing IVIg treatment.DiscussionCIDP may be associated with tacrolimus use in organ transplantation and can occur after years of treatment. IVIg was usually effective in our cohort, and in those who switched to alternative immunosuppression, there was no evidence of active disease after initial treatment.
Cancer antigen-125 and risk of atrial fibrillation: a systematic review and meta-analysis
Background Cancer antigen-125 (Ca-125) is traditionally recognised as a tumour marker and its role in cardiovascular diseases has been studied only in recent years. Whether Ca-125 is elevated in patients with atrial fibrillation (AF) and its levels predict the risk of AF remains controversial. Therefore, we conducted a systematic review and meta-analysis of the association between Ca-125 levels and AF. Methods PubMed and EMBASE databases were searched until 1 June 2017 for studies that evaluated the association between Ca-125 and AF. Inclusion criteria included studies that compare Ca-125 in patients with and without AF, or those reporting HRs/ORs for risk of AF stratified by Ca-125 levels. Results A total of 39 entries were retrieved from the databases, of which 10 studies were included in the final meta-analysis. Ca-125 was significantly higher in patients with AF compared with those in sinus rhythm (mean difference=16 U/mL, 95% CI 2 to 30 U/mL, P<0.05; I2: 98%). Ca-125 significantly increased the risk of AF (HR: 1.39, 95% CI 1.06 to 1.82, P<0.05; I2: 84%). Conclusion Ca-125 was significantly higher in patients with AF than in those in sinus rhythm, and high Ca-125 is predictive of AF occurrence. However, the high heterogeneity observed means there is an uncertainty in the relationship between Ca-125 and AF, which needs to be confirmed by larger prospective studies.
Peripherin is a biomarker of axonal damage in peripheral nervous system disease
Abstract Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.
Investigating Different Levels of Bimanual Interaction With a Novel Motor Learning Task: A Behavioural and Transcranial Alternating Current Stimulation Study
Many tasks require the skilled interaction of both hands, such as eating with knife and fork or keyboard typing. However, our understanding of the behavioural and neurophysiological mechanisms underpinning bimanual motor learning is still sparse. Here, we aimed to address this by first characterising learning-related changes of different levels of bimanual interaction and second investigating how beta tACS modulates these learning-related changes. To explore early bimanual motor learning, we designed a novel bimanual motor learning task. In the task, a force grip device held in each hand (controlling x- and y-axis separately) was used to move a cursor along a path of streets at different angles (0°, 22.5°, 45°, 67.5°, and 90°). Each street corresponded to specific force ratios between hands, which resulted in different levels of hand interaction, i.e., unimanual (Uni, i.e., 0°, 90°), bimanual with equal force (Bieq, 45°), and bimanual with unequal force (Biuneq 22.5°, 67.5°). In experiment 1, 40 healthy participants performed the task for 45 min with a minimum of 100 trials. We found that the novel task induced improvements in movement time and error, with no trade-off between movement time and error, and with distinct patterns for the three levels of bimanual interaction. In experiment 2, we performed a between-subjects, double-blind study in 54 healthy participants to explore the effect of phase synchrony between both sensorimotor cortices using tACS at the individual’s beta peak frequency. The individual’s beta peak frequency was quantified using electroencephalography. 20 min of 2 mA peak-to-peak amplitude tACS was applied during task performance (40 min). Participants either received in-phase (0° phase shift), out-of-phase (90° phase shift), or sham (3 s of stimulation) tACS. We replicated the behavioural results of experiment 1, however, beta tACS did not modulate motor learning. Overall, the novel bimanual motor task allows to characterise bimanual motor learning with different levels of bimanual interaction. This should pave the way for future neuroimaging studies to further investigate the underlying mechanism of bimanual motor learning.
Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen–Glucose Deprivation Conditions
Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen–glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT’s potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT’s precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection.
Human motor cortical gamma activity relates to GABAergic intracortical inhibition and motor learning
Abstract Gamma activity (γ, >30 Hz) is universally demonstrated across brain regions and species. However, the physiological basis and functional role of γ sub-bands (slow-γ, mid-γ, fast-γ) have been predominantly studied in rodent hippocampus; γ activity in the human neocortex is much less well understood. We use electrophysiology, non-invasive brain stimulation, and several motor tasks to examine the properties of sensorimotor γ activity sub-bands and their relationship with both local GABAergic activity and motor learning. Data from three experimental studies are presented. Experiment 1 (N = 33) comprises magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), and a motor learning paradigm; experiment 2 (N = 19) uses MEG and motor learning; and experiment 3 (N = 18) uses EEG and TMS. We characterised two distinct γ sub-bands (slow-γ, mid-γ) which show a movement-related increase in activity during unilateral index finger movements and are characterised by distinct temporal–spectral–spatial profiles. Bayesian correlation analysis revealed strong evidence for a positive relationship between slow-γ (~30–60 Hz) peak frequency and GABAergic intracortical inhibition (as assessed using the TMS-metric short interval intracortical inhibition). There was also moderate evidence for a relationship between the power of the movement-related mid-γ activity (60–90 Hz) and motor learning. These relationships were neurochemical and frequency specific. These data provide new insights into the neurophysiological basis and functional roles of γ activity in human M1 and allow the development of a new theoretical framework for γ activity in the human neocortex.
A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning
Key points Baclofen is a GABAB agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. Overall baclofen did not alter transcranial magnetic stimulation‐measured GABAB inhibition, although the change in GABAB inhibition correlated with aspects of visuomotor learning retention. Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients. AbstractThe GABAB agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double‐blind, placebo‐controlled study, we investigated whether a single 10 mg dose of the GABAB agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABAA (short‐interval intracortical inhibition, 2.5 ms) and GABAB (long‐interval intracortical inhibition, 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F1,137.8 = 6.133, P = 0.014) and retention (F1,130.7 = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABAB inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.